To obtain drug effects from a drug by its administration, an oral administration method is generally used; however, transdermal administration methods have many advantages over oral administration methods. For example, in an oral administration method, the drug absorbed in the bowel is, before it exhibits a drug effect in a desired site, first metabolized in the liver and most of its quantity is decomposed; whereas in a transdermal administration method, since the absorbed drug does not first pass through the liver during its body circulation, the drug effect is not significantly reduced by the metabolism in the liver. Moreover, transdermal administration methods have further advantages that drug effects are long lasting, and the methods have a certain type of drug-release characteristics.
Furthermore, as an advantage of transdermal administration methods, alleviation of side effects by maintaining a constant blood concentration of the drug through its sustained release is expected. In particular, there is a tendency that transdermal administration preparations that can be administered over a long period of time (1 day to 7 days) are preferred from the viewpoint of compliance of patients. To make such a long-term (1 day to 7 days) administration preparation, an effective amount of the drug must be absorbed transdermally during the administration period; accordingly, a large amount of the drug must be retained in the preparation. Considering the practicable area and thickness of preparations, it is necessary that the highest possible concentration (at least 10 mass % or more, preferably 20 mass % or more, and more preferably 30 mass % or more) of a drug is contained in a preparation. However, because many basic drugs are low soluble to rubber adhesives and silicone adhesives, it is very difficult to contain a basic drug with 10 mass % or more in these adhesives while maintaining properties of the adhesives. Meanwhile, to produce a transdermal administration preparation comprising a basic drug with the high concentration of 10 mass % or more, use of an acrylic adhesive having high polarity is advantageous in terms of solubility to drugs; however, many basic drugs react with acrylic acid alky ester or acrylic acid, i.e., a constitutional monomer of acrylic adhesives, possibly leading to a problem of a decrease in the drug content, etc.
Bisoprolol is a basic drug, which is a β blocker that selectively blocks β1 receptors of the sympathetic nervous system, does not have an intrinsic sympathomimetic effect, and is a therapeutic drug of essential hypertension.
Currently, bisoprolol is used only in the form of oral preparation in clinical setting, and has relatively small effects on bronchial tubes due to its high selectivity for β1. However, when bisoprolol is orally administered, it may possibly induce symptoms such as bradycardia, dizziness, and malaise; from the viewpoint of stability of blood concentration over long period of time and sustainability of effects, development of transdermal administration preparations such as adhesive patches has been desired, rather than oral administration.
Fluvoxamine is a basic drug as well, which is a selective serotonin reuptake inhibitor (SSRI) acting on the re-absorption of serotonin in the synapse, and is an antidepressant.
When SSRI such as fluvoxamine is orally administered to a patient, side effects such as nausea, diarrhea, and gastrointestinal tract disturbance are concerned, and defect of decreased compliance occurs such as withdrawal of taking the drug. Therefore, methods for administration other than oral administration are investigated in recent years.
Considering such a current situation, making a transdermal preparation comprising bisoprolol, in particular making an adhesive patch, has been proposed (Patent Literatures 1-4). For example, Patent Literature 4 discloses a transdermal preparation that can transdermally administer a drug stably for a long period of time, by laminating a skin adhesion layer onto a backing and a drug reservoir layer comprising bisoprolol. However, since an acrylic adhesive is used for the drug reservoir layer, the drug content tends to decrease during long period of storage.
Furthermore, Patent Literature 5 discloses an adhesive patch comprising a selective serotonin reuptake inhibition constituent as a pharmacologically-active component. However, in this literature, it is not that a basic drug is contained in a high concentration by means of comprising water-soluble polymer in the adhesive patch, and a means for achieving this is not provided as well.
Moreover, in Patent Literature 6, a transdermal therapeutic device having at least three layers consisting of a drug-non-penetrating backing layer, a drug reservoir layer comprising a serotonin receptor antagonist positioned between the backing layer and a drug-release layer, and the drug-release layer consisting of a pressure-sensitive adhesive layer that can control release of the drug. However, this literature neither enables to contain a basic drug in a high concentration, nor provides a means for achieving this.